Over the past two decades, human immunodeficiency virus type 1 has placed an enormous socioeconomic burden on the global population. The ultimate ambition of HIV-1 research is to eradicate the virus from infected individuals and devise strategies to limit its spread amongst the human population. Unfortunately, this arduous ambition may be further complicated by the fact that HIV-1 appears to target the central nervous system (CNS) early after peripheral infection, giving rise to unwieldy neurologic complications in 30-60% of patients. HIV-1 also has the capacity to cripple the immune system and open the floodgates for opportunistic secondary infections that can also seek refuge in the immunologically specialized CNS. Because the CNS is fraught with mechanisms to limit the toxicity (and likely the effectiveness) of an immune response, it often provides a favorable environment for persistent pathogens. Consequently, once a pathogen establishes persistence in the CNS, it may become far more challenging to purge the pathogen from this compartment than peripheral tissues. Thus, even if researchers accomplish the monumental task of attaining sterilizing immunity in peripheral tissues, it is likely that HIV-1 and/or other opportunistic infections will continue to persist in the CNS and contribute to neurologic abnormalities. The proposed study will explore a novel murine model of CNS viral persistence to address whether it is possible for the host immune response to purge an infection once it has established persistence in the CNS. Contemporary T cell tracking methodologies will be utilized to monitor the migration and interactions of virus-specific T cells in the CNS following reactivation in the periphery (a scenario that we hope to achieve in humans). The proposed study will also explore adoptive immunotherapy as a strategy to assist the endogenous host response in its pursuit to eliminate persistently infected CNS cells. The main objective of this research is to define the immunologic parameters that contribute to viral clearance versus persistence in the CNS and foster approaches that tip the balance in favor of clearance.